Since the discovery of norfloxacin, antibacterial activity and pharmacokinetics of synthetic quinolone antibacterial agents have been sharply improved, and many compounds are now used in the clinical field as chemotherapeutic agents which are effective in almost systemic infectious diseases.
In recent years, generation of bacteria having low sensitivity to synthetic quinolone antibacterial agents has been increasing in the field of clinics. For example, like the case of Staphylococcus aureus (MRSA) and pneumcoccus (PRSP) which are non-sensitive to β-lactam antibiotics and enterococcaus (VRE) which is non-sensitive to aminoglycoside antibacterial agents, a case has been increasing in which a Gram-positive bacterium originally resistant to drugs other than synthetic quinolone antibacterial agents also became low-sensitive to synthetic quinolone antibacterial agents. In consequence, development of a drug having further high efficacy has been called for in the field of clinics.
Also, a side effect in which convulsions are induced when a non-steroidal anti-inflammatory drug is simultaneously used, as well as other side effects such as phototoxicity and the like, have been revealed, so that development of a synthetic quinolone antibacterial agent having further high safety has also been called for in the field.
It is known that structures of substituents at the 7-position and 1-position are greatly concerned in the antibacterial activity, pharmacokinetics and safety of synthetic quinolone antibacterial agents. It is already known that a quinolone derivative having 3-(aminomethyl) pyrrolidinyl group as the 7-position substituent shows strong antibacterial activity for Gram-negative and Gram-positive bacteria. For example, there is a 7-[3-(aminomethyl)pyrrolidin-1-yl)quinolonecarboxylic acid derivative [Journal of Medicinal Chemistry, vol. 29, p. 445 (1986)]. Also, a 7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [Journal of Medicinal Chemistry, vol. 36, p. 871 (1993)], a 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [Journal of Medicinal Chemistry, vol. 37, p. 733 (1994)] a 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [Chemical & Pharmaceutical Bulletin, vol. 42, p. 1442(1994)] and the like are known as quinolonecarboxylic acid derivatives having a substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group.
However, substituents on the aminomethyl group of currently known 3-(aminomethyl)pyrrolidin-1-yl group are only alkyl groups, and a quinolone compound having an aromatic group as a substituent, which is related to the present invention, is not known.
Also, as a reference in which quinolonecarboxylic acid derivatives having a cyclic substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group are exemplified, there is, for example, JP-W-3-502452 (the term “JP-W” as used herein means an “unexamined published Japanese international patent application”), and it describes compounds represented by two general formulae shown below. However, the cyclic substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group described in this document is limited to a cyclic alkyl, and there is no disclosure on the 3-[1-amino-1-aromatic group-substituted]methylpyrrolidin-1-yl group related to the invention.
[In the above formula, R12 is an alkyl group having from 1 to 4 carbon atoms, a vinyl group, a haloalkyl group, a hydroxyalkyl group having from 2 to 4 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, phenyl group or a phenyl group substituted with a halogen, an alkyl group, NH2 or OH, R14 is a straight, branched or cyclic lower alkyl group having from 1 to 3 carbon atoms, and X3 is CH, CF, CCl, CBr, N, CCF3, CNH2, CNO2, CR or COR′ (in these formulae, R is a lower alkyl group and R′ is hydrogen atom or a lower alkyl group).]
In the above formula, Z is
(wherein m is an integer of from 0 to 4, and R15 and R16 are each independently a hydrogen atom, a lower alkyl group or a cycloalkyl group). In this connection, the definitions of substituents and the like in the above two general formulae are unrelated to those of the of the invention, even if the same symbols are used.
In addition, JP-W-9-503783 discloses 2-pyridone carboxylic acid derivatives of 4H-4-oxoquinolizone skeleton and the like shown by the following formula. However, the quinolone compound of the invention having an aromatic substituent on the aminomethyl group moiety of 3-(aminomethyl)pyrrolidin-1-yl group related to the invention is not also exemplified in this document.
